WNTFrizzled Interactions

In mammals, 10 FZDs and 19 WNTs have been identified. This allows a large number of putative ligand-receptor pairs and raises the question of what structural determinants govern WNT/FZD selectivity [21]. In Drosophila melanogaster, 4 FZDs (Fz, DFz2, 3, 4) and 5 WNTs (wingless, Wg; DWNT2, 3, 4, 8) were described, and their interaction profiles have been determined [22] and suggest a rather specific pattern of FZD-WNT interactions in higher organisms. So far, very few WNTs have been purified and extensively tested in their active form [23, 24]. Because of this, hardly any quantitative pharmacological information on affinity constants, binding kinetics or dose-effect relationships is available [22, 25, 26]. In the cited studies, affinities of WNTs to FZD-CRDs were found to be in the lower nanomolar range both in cell-free and cell-based assays. For example, the interaction between Xenopus WNT- 8 and mouse FZD8-CRD showed a dissociation constant Kd = 8nM [25]. When discussing the role of the CRD for FZD binding to WNTs, it is important to mention results indicating that the CRD might actually not be required for WNT signal transmission [27] i Thus, CRD binding of WNTs could serve merely as a means of recruiting WNTs to the receptor, whereas WNT interaction with parts of the FZD extracellular loops and core region is necessary for signal transduction i27, 28] and establishment of a highi affinity ligand-receptor complex. Another level of complexity was added by a study reporting the dimerization of FZD even in the absence of the CRD [29].

The availability of purified and active WNTs galvanized the research field: these tools allowed more controlled stimulation of WNT pathways as well as a more quantitative analysis of dose-effect relationships [30, 31]. This is important because the broad expression of FZDs in various cell types renders a pharmacological and cell-based analysis of single WNT-FZD pairs difficult. In fact, we have not been able to identify a suitable mammalian cellular system without endogenous FZD expression. On the contrary, many cell types express multiple isoforms as well as co-receptors (unpublished observations).